Ion channels are pore-forming proteins that help establish and control a small voltage gradient across the plasma membrane of living cells by allowing the flow of ions down their electrochemical gradient. One type of ion channel is a voltage-gated channel, which utilizes a change in the voltage across the membrane to open the ion channel.
In nerve and skeletal muscle cells, a stimulus that causes sufficient depolarization promptly causes voltage gated sodium channels (VGSCs) to open, allowing a small amount of Na+ to enter the cell down its electrochemical gradient. The influx of positive charge depolarizes the membrane further, thereby opening more Na+ channels, which admit more Na+ ions, causing still further depolarization.
In this way, VGSCs provide the sodium ion currents that allow excitable cells, such as cardiac muscle and nerve cells, to “fire” digital pulses called action potentials. At most moments in time, these channels are closed and nonconducting, and only open briefly when a cell's membrane is depolarized. Within milliseconds, VGSCs then undergo fast inactivation—a separate non-conducting state from which channels recover within milliseconds after membrane repolarization. VGSCs contain a so-called fast inactivation “particle” (or “gate”) that binds to the open channel pore to induce inactivation. The cycle of Closed—fast→Open—fast→Inactivated—fast→Recovered states of VGSCs enables them to fuel firing of action potentials at high frequencies in some cells.
There have been attempts to induce inactivation of VGSCs. However, these methods often destroy the entire VGSC. Other methods block various types of ion channels without being channel specific.
Accordingly, there remains a need for a peptide capable of inducing long-term use-dependent inactivation selectively in VGSCs. Such a peptide has a therapeutic value for cardiac and neurological disorders characterized by high frequency firing rates.